Molecular Composition and Pathology of Entheses on the Medial And

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1015 Ann Rheum Dis: first published as 10.1136/ard.2003.016378 on 12 August 2004. Downloaded from EXTENDED REPORT Molecular composition and pathology of entheses on the medial and lateral epicondyles of the humerus: a structural basis for epicondylitis S Milz, T Tischer, A Buettner, M Schieker, M Maier, S Redman, P Emery, D McGonagle, M Benjamin ......

Ann Rheum Dis 2004;63:1015–1021. doi: 10.1136/ard.2003.016378

Objectives: To improve the understanding of epicondylitis by describing the normal structure and composition of the entheses associated with the medial and lateral epicondyles and their histopathology in elderly cadavers. Methods: Medial and lateral epicondyles were obtained from 12 cadavers. Six middle aged cadavers (mean 47 years) were used to assess the molecular composition of ‘‘normal’’ entheses from people within an age range vulnerable to epicondylitis. Cryosections of epicondylar entheses were immunolabelled with monoclonal antibodies against molecules associated with fibrocartilage and related tissues. A further six See end of article for elderly cadavers (mean 84 years) were used for histology to assess features of entheses related to authors’ affiliations increasing age...... Results: Tendon entheses on both epicondyles fused with those of the collateral ligaments and formed a Correspondence to: more extensive structure than hitherto appreciated. Fibrocartilage (which labelled for type II collagen and Professor M Benjamin, aggrecan) was a constant feature of all entheses. Entheses from elderly subjects showed extensive School of Biosciences, Cardiff University, Museum microscopic damage, hitherto regarded as a hallmark of epicondylitis. Avenue, Cardiff CF10 Conclusions: Fibrocartilage is a normal feature and not always a sign of enthesopathy. Furthermore, 3US, UK; benjamin@ pathological changes documented in patients with epicondylitis may also be seen in elderly people. The cardiff.ac.uk fusion of the common extensor and flexor tendon entheses with those of the collateral ligaments suggests Accepted1December2003 that the latter may be implicated as well. This may explain why pain and tenderness in epicondylitis may ...... extend locally beyond the tendon enthesis and why some patients are refractory to local treatments.

espite the widespread clinical awareness of epicondy- (a) whether fibrocartilage was always a typical feature of litis and the appreciation that it is a degenerative rather epicondylar tendon entheses; (b) the anatomical relationship than inflammatory condition,1 little is known about the between the tendon entheses and those of the collateral

D http://ard.bmj.com/ normal structure of the tendon entheses involved, or of their ligaments, and whether these can be distinguished by their precise relationship with the entheses of the collateral molecular composition; (c) what morphological evidence of ligaments of the elbow joint. This makes interpretation of degeneration was present in the entheses of elderly people, tendon biopsies from patients with epicondylitis difficult and and how the degenerative changes compare with those contributes to a poor clinical understanding of this condition. described by other authors for epicondylitis. Epicondylitis is usually associated with the tendons of the common extensor and flexor origins,12yet both of these are intimately related to the collateral ligaments, as evidenced MATERIALS AND METHODS on September 28, 2021 by guest. Protected copyright. by gross dissections3 or magnetic resonance imaging.4 Entheses in middle aged people Furthermore, rheumatologists, radiologists, and surgeons Six cadavers of both sexes and of mean age 47 years (range alike have acknowledged degenerative changes in adjacent 30–62) were used to assess the tissue type and molecular tissues, including those of the collateral and annular composition of ‘‘normal’’ entheses typical of people within ligaments.4–6 the age range most commonly associated with epicondy- Pathological studies have emphasised the presence of litis. The specimens were obtained from cadavers in fibrocartilage as a marker of degenerative change, both in the Department of Forensic Medicine (Institut fu¨r diseased epicondylar entheses and at other sites.7–10 However, Rechtsmedizin, Ludwig-Maximilians-Universita¨t) in accor- there is also much evidence to suggest that fibrocartilage is a dance with the ethical regulations of Munich University. The normal feature of many entheses—particularly those at the lateral and medial epicondyles from one limb, together with ends of long bones.11 12 The four zones of tissue at a their associated tendon and collateral ligament entheses, fibrocartilaginous enthesis (dense fibrous connective tissue, were fixed for 24 hours in 90% methanol at 4˚C. The tissue uncalcified fibrocartilage, calcified fibrocartilage, and bone) was decalcified in 5% EDTA, rinsed in phosphate buffered are thought to provide a gradual change in mechanical saline (PBS), infiltrated for 12 hours with a 5% sucrose properties at the insertion site, so that stress concentration is solution in PBS, and sectioned on an HMV500 Microm dissipated and the risk of failure reduced.13–15 cryostat at 12 mm. A radiograph of each specimen was taken The purpose of this study was to define the normal before decalcification and the plane of section was as structure and molecular composition of the entheses asso- described above. ciated with the medial and lateral epicondyles, and to document the pathological changes to which they are subject. We used two different age groups (middle aged and elderly) Abbreviations: LCL, lateral collateral ligament; MCL, medial collateral to fulfil our objectives and specifically sought to determine ligament; PBS, phosphate buffered saline

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Figure 1 Frontal longitudinal sections of a normal elbow joint from a Figure 2 A schematic representation of the enthesis organs associated 30 year old man. (A) The radial (lateral) part of the joint showing the with the medial and lateral epicondyles based on fig 1. The elbow is thus tendinous attachment (T) of the common extensor origin to the lateral drawn in coronal (frontal) section with the humerus located proximally epicondyle and the attachment of the lateral collateral ligament (L) with and the radius and ulna distally. Both the articular cartilages of the elbow which it was directly continuous. Note that the collateral ligament merges (AC1) and superior radioulnar (AC2) joints are visible. (A) The lateral with the annular ligament (arrow), which in turn wraps around the head epicondyle. The lateral collateral ligament (L) fuses with the annular of the radius (R). Note also the presence of muscle fibres (MF) attaching ligament (AL), which in turn wraps around the radial head at the position to both the tendon and the collateral ligament. H, humerus; U, ulna. of the arrow. The common extensor tendon (T) lies immediately lateral to Inset—the lateral epicondyle from a 47 year old man with a small bony the collateral ligament and the entheses of these two structures are fused. spur (arrow) at the tendon enthesis. (B) The ulnar (medial) part of the The single fused enthesis serves to dissipate stress concentration between same specimen that is featured in (A). The tendinous attachment (T) of the tendon and ligament at the bony interface and stress is further reduced common flexor origin is directly continuous with the medial collateral by the contact between annular ligament and radial head (arrow). ligament (M). Note that the ligament wraps around the articular cartilage Consequently, the enthesis organ comprises the tendon, collateral at the edge of the trochlea (arrow) at the lower end of the humerus (H) ligament, annular ligament, and the adjacent circumference of the radial and that again there are muscle fibres (MF) attaching to both the tendon head. (B) The medial epicondyle. The medial collateral ligament (M) and the medial collateral ligament. U, ulna; Scale bars = 0.9 cm. fuses with the tendon (T) of the common flexor origin at its enthesis and the former presses against the articular cartilage on the edge of the humerus at the position of the arrow. The enthesis organ thus consists of Immunohistochemistry the tendon, collateral ligament, and a part of the humeral articular Sections from the middle aged subjects were immunolabelled cartilage. with a panel of primary monoclonal antibodies directed against collagens (types I, II, III, and VI), glycosaminoglycans (chondroitin-4- and -6-sulphates, keratan and dermatan section ensured that both the tendon of the common sulphates), and proteoglycans (aggrecan, link protein, versi- extensor or flexor origins and the associated lateral/medial http://ard.bmj.com/ can, and tenascin). Details of the primary antibodies collateral ligaments of the elbow were present in the slides (sources, dilutions, and enzyme pretreatments) have been examined (fig 1). given previously.16 Endogenous peroxidase activity was blocked by pretreating sections with 0.3% hydrogen peroxide RESULTS in methanol, and non-specific binding of the secondary The tendon attachments to both epicondyles were directly antibody (horse antimouse; provided in the Vectastain ABC continuous with those of the collateral ligaments as indicated

‘‘Elite’’ avidin/biotin/peroxidase detection kit) was reduced in the gross section of the normal elbow of a 30 year old man on September 28, 2021 by guest. Protected copyright. by treating the sections with horse serum. Control sections illustrated in fig 1. Figure 2 shows a schematic representation were made by omitting the primary antibody. of this section. In all specimens the epicondylar attachment sites of both the flexor and extensor muscles of the forearm Entheses in elderly people blended imperceptibly with the humeral attachments of the To assess the pathological features of epicondylar entheses medial (MCL) and lateral collateral (LCL) ligaments (fig 1A). associated with elderly people, the lateral and/or medial Thus, as a result of the fusion between ligament and tendon epicondyles together with their associated entheses were at the attachments to each epicondyle, there was a single removed from six dissecting room cadavers (donated to enthesis with no boundary between the two structures which Cardiff University) of both sexes (mean age 84 years; range formed it. Elsewhere, each tendon and its adjacent ligament 78–101) that had been perfused with a solution containing could be more easily distinguished. As both ligaments also formaldehyde and alcohol. Details of this have been given pressed against articular cartilage, and the LCL was attached previously.17 Although none of the cadavers selected showed to the annular ligament (figs 1A, 2, 3A), the fused tendon- any apparent gross abnormality in the elbow region, the use ligament attachment sites on either side of the elbow, each of elderly dissecting room specimens increased the likelihood formed part of an ‘‘enthesis organ’’ that dissipated stress of finding degenerative changes at the entheses. All speci- concentration over a broad area. mens were postfixed for 1 week in 10% neutral buffered In three of the six specimens from middle aged subjects, a formal saline, decalcified in 5% nitric acid, dehydrated with small bony spur (enthesophyte) was present at the proximal graded alcohols, cleared in xylene, and embedded in paraffin part of the attachment of the common extensor origin (fig 1A wax. Radiographs were taken before decalcification. After inset). These spurs were also visible in the accompanying histological processing, longitudinal sections of each epicon- radiographs (not illustrated). However, no spurs were found dylar enthesis were cut in the coronal (frontal) plane at 8 mm in any of the specimens from the medial side of the elbow. In and stained with Masson’s trichrome. The chosen plane of all specimens, both the medial and lateral epicondylar

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Figure 3 Routine histology and histopathology of the medial and lateral epicondylar entheses. (A) A low power view (frontal section) of the single enthesis on the lateral epicondyle from a 101 year old woman that is formed by the fusion of the tendon (T) of the common extensor origin with the lateral collateral ligament (L) of the elbow joint. The tendon and collateral ligament similarly fuse with each other at the medial epicondylar enthesis (not illustrated). Note that the lateral collateral ligament is also fused with the annular ligament (AL) that wraps around around the head of the radius (not visible in the section). Note also the presence of only a thin layer of subchondral bone (arrows) throughout the enthesis and the small bony spur (S) at the proximal end of the tendon attachment. AC, articular cartilage. Scale bar = 0.2 cm. (B, C) Fibrocartilage at the attachment of both the tendon (B) and the ligament (C) to the lateral epicondyle in the same specimen featured in (A). The fibrocartilage is equally prominent at both sites and consists of zones of uncalcified (UF) and calcified (CF) tissue separated by a calcification front known as the tidemark (TM). B, bone. Scale bars = 50 mm. entheses were moderately fibrocartilaginous, and zones of Molecular composition of the entheses uncalcified and calcified fibrocartilage separated by one or Table 1 summarises the molecular composition of the more tidemarks were clearly visible in both middle aged and entheses and features of special interest are described below elderly subjects (figs 3B, and C). The underlying layer of and illustrated in Figs 4A–S. In both the tendon and ligament subchondral bone was thin (generally ,150 mm) and thus parts of the lateral epicondylar enthesis, the uncalcified and most of the bone at the entheses was cancellous (fig 3A). calcified fibrocartilage zones immunolabelled for type II http://ard.bmj.com/

Table 1 Summary of the immunohistochemical labelling characteristics of the entheses associated with the lateral and medial epicondyles

Collagens Glycosaminoglycans Proteoglycans and glycoproteins

I II III VI KS DS, C4S C4S C6S Agg Link Versican Tenascin on September 28, 2021 by guest. Protected copyright. Lateral epicondyle Tendon attachment Bone matrix 6006 0 0000 0 0 0 Fibrocartilage 6* 666666666 6* 6* Fibrous zone 6366 6 6643 3 6 4

Ligament attachment Bone matrix 6006 0 0000 0 0 0 Fibrocartilage 6* 666666666 6* 6* Fibrous zone 6366 6 6643 3 6 4

Medial epicondyle Tendon attachment Bone matrix 6006 0 0000 0 0 0 Fibrocartilage 6666 6 6666 6 6 6 Fibrous zone 6366 6 6632 3 6 4

Ligament attachment Bone matrix 6006 0 0000 0 0 0 Fibrocartilage 6666 6 6666 6 6 6 Fibrous zone 6366 6 6612 3 6 4

The figures indicate the number of specimens (maximum six) in which positive labelling was seen. There was no distinction between the labelling patterns of the calcified and uncalcified zones of fibrocartilage with any antibody, but only the outer (and not the inner) part of the zone of uncalcified fibrocartilage labelled for type I collagen, versican, and tenascin in the lateral epicondylar entheses*. Agg, aggrecan; C4S, chondroitin-4-sulphate; C6S, chondroitin-6-sulphate; DS, dermatan sulphate; KS, keratan sulphate; Link, link protein.

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Figure 4 Immunohistochemical labelling of the medial and lateral epicondylar entheses. (A, B) Extensive labelling of fibrocartilage for type II collagen (asterisk) at both the tendon (A) and ligament (B) parts of the lateral epicondylar enthesis. B, bone; DF dense fibrous connective tissue. Scale bars = 500 mm. (C) Strong labelling for type II collagen (arrows) in the region of the medial collateral ligament close to the enthesis, where it wraps around the edge of the humeral articular cartilage. The region illustrated is that indicated by the arrow in fig 1B. Note that only the surface of the ligament is labelled. Scale bar = 100 mm. (D) At the lateral epicondylar enthesis, labelling of the ‘‘wrap-around’’ region of the lateral collateral ligament (that is, where it was in contact with the head of the radius—see arrow in fig 1A) for type II collagen was seen not only at the ligament surface but also in the underlying tissue. Scale bar = 100 mm. (E, F) Aggrecan labelling (asterisk) of fibrocartilage at the ligament (E) and tendon (F) parts of the medial epicondylar enthesis. B, bone. Scale bars = 500 mm. (G, H) Aggrecan labelling (asterisk) of fibrocartilage at the ligament (G) and tendon (H) parts of the lateral epicondylar enthesis. B, bone. Scale bars = 250 mm. (I) Intense labelling for aggrecan at the surface (arrow) of the ‘‘wrap-around’’ region of the lateral collateral ligament (that is, where it was in contact with the head of the radius—see arrow in fig 1A). Scale bar = 50 mm. (J, K) Labelling for link protein (asterisk) in fibrocartilage at both the ligament (J) and tendon (K) parts of the lateral epicondylar enthesis. B, bone. Scale bars = 500 mm. (L) Chondroitin-6-sulphate labelling (asterisk) in fibrocartilage in the tendon part of the medial epicondylar enthesis. B, bone. Scale bar = 100 mm. (M) Chondroitin-6-sulphate labelling (asterisk) in fibrocartilage in the ligament part of the lateral epicondylar enthesis. B, bone. Scale bar = 100 mm. (N) Strong labelling for chondroitin-6-sulphate (arrow) in the region of the lateral collateral ligament close to the enthesis, where it wraps around the head of the radius. The region illustrated is that indicated by the arrow in fig 1A. Scale bar = 50 mm. (O) Type I collagen labelling in the ligament part of the lateral epicondylar enthesis. Note the strong labelling of both the dense fibrous zone of the ligament enthesis (DF) and the bone (B), but the absence of labelling from the calcified (CF) and much of the uncalcified enthesis fibrocartilage (UF). The dotted line indicates the position of the tidemark. Scale bar = 500 mm. (P) Versican labelling in the ligament part of the lateral epicondylar enthesis. Labelling is present in the dense fibrous zone (DF), part of the adjacent zone of uncalcified fibrocartilage (UF), and the zone of calcified fibrocartilage (CF). However, labelling was largely absent from the deeper part of the zone of uncalcified fibrocartilage (asterisk). B, bone. Scale bar = 250 mm. (Q) Low power view of type II collagen labelling (asterisk) of fibrocartilage at the surface of a small bony spur (BS) in the tendon (T) part of the lateral epicondylar enthesis. Scale bar = 500 mm. (R) High power view of the region enclosed in the rectangle in (Q) showing a small venule (V) packed with blood cells, passing between tendon and bone in the type II collagen positive region (asterisk). Scale bar = 250 mm. (S) Strong labelling for link protein (asterisk) around the tip of the bony spur (BS) featured in (Q) and (R) and in the uncalcified fibrocartilage (UF) of the tendon. A similar labelling pattern was also evident for aggrecan. Scale bar = 500 mm.

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Figure 5 (A) Prominent fissures (*) at the ligament end of the medial epicondylar enthesis that greatly disrupt the normal structure of the attachment

site. UF, uncalcified fibrocartilage; arrows, tidemarks. Scale bar = 500 mm. (B) Higher power view of several fissures from the same specimen as http://ard.bmj.com/ illustrated in (A) to show the prominent layer of fibrin (arrows) on the surface of the fissures. Scale bar = 50 mm. (C) Clusters of fibrocartilage cells (arrows) separated by small regions of acellular matrix (asterisk) in the tendon part of a lateral epicondylar enthesis. Scale bar = 50 mm. (D) Fibrocartilage cell proliferation (arrows) at the tendon attachment on the lateral epicondylar enthesis. B, bone. Scale bar = 100 mm. (E) Small foci of calcified tissue and fibrocartilage cell clusters in the zone of uncalcified fibrocartilage at the medial epicondylar enthesis. Scale bar = 50 mm. (F) Numerous small blood vessels (BV), indicating vascular proliferation at the site of a small bony defect (arrow) in the tendon attachment on the medial epicondylar enthesis. The blood vessels are passing between the tendon and the bone marrow. Scale bar = 100 mm. (G) A section adjacent to that featured in fig 2A to show the presence of fibrocartilage (FC) at the tip of the small bony spur (S). (H) A small region of fibrocartilage (FC) within the bone marrow, between neighbouring bone spicules (B). Scale bar = 50 mm. (I) A subchondral bone cyst (C) beneath the tendinous part of the lateral epicondylar enthesis. B, bone; FC, fibrocartilage. Scale bar = 500 mm. (J) A venule in the bone marrow associated with the tendinous part of the lateral on September 28, 2021 by guest. Protected copyright. epicondylar enthesis. Note the presence of inflammatory cells around the vessel (arrows) and of several marginating leucocytes around the edge of the lumen (arrowheads). Scale bar = 50 mm. (K) Evidence of bone marrow fibrosis (F) in the same specimen as (J). B, bone. Scale bar = 100 mm. All sections were stained with Masson’s trichrome. collagen, chondroitin-6-sulphate, aggrecan, and link protein aggrecan, and link protein) was less extensive than in the (figs 4A, B, G, H). In three cadavers, aggrecan and link lateral epicondylar enthesis (figs 4E and F). Furthermore, protein labelling extended into the fibrous zones of both the there was local absence of type I collagen, tenascin, and ligament and tendon, away from the insertion site. This was versican labelling on the lateral but not the medial especially evident in the region where the LCL passed over epicondylar enthesis, and no bony spurs were seen in any the edge of the radial head (fig 4D). Although type I collagen, specimens at the latter location. The MCL showed some tenascin, and versican labelling were widespread in the mid- evidence of fibrocartilage differentiation where the ligament substance of the LCL, labelling for these molecules was passed over the edge of the humeral articular cartilage sometimes absent in its fibrocartilage zones. The bony spurs (fig 4C). Here, the tissue labelled for type II collagen, seen in three cadavers were located in the most proximal aggrecan, and link protein. parts of the lateral epicondylar enthesis—that is, in association with the tendon part of the attachment site. They were Enthesis histopathology surrounded by fibrocartilage that labelled as described above. Signs of degenerative change were common in both the In general, the molecular composition of the medial ligament and tendon entheses on either side of the elbow. epicondylar enthesis was similar to that described for the The organised enthesis structure was most strikingly dis- lateral epicondyle. However, labelling for typical fibrocarti- rupted by the presence of numerous fissures (fig 5A). The lage molecules (type II collagen, chondroitin-6-sulphate, edges of these were sometimes lined by a layer of brightly

www.annrheumdis.com 1020 Milz,Tischer,Buettner,etal Ann Rheum Dis: first published as 10.1136/ard.2003.016378 on 12 August 2004. Downloaded from staining fibrin (figs 5B). Chondrocytic clusters and signs of We view enthesis fibrocartilage as a sign of normal fibrocartilage cell proliferation were also a striking feature of functional adaptation of the epicondylar attachment sites some of the material from the elderly subjects (figs 5C and D) that reduces the risk of wear and tear.11–15 As at entheses and there were small foci of intratendinous calcification elsewhere in the body,11 12 fibrocartilage promotes stress (fig 5E). Areas where several small blood vessels were dissipation at the hard-soft tissue interface by enabling them aggregated together near the bony interface suggested to withstand compression and/or shear forces. This is vascular proliferation and the potential for some vessels in reflected by its molecular composition—that is, the pres- the tendon/ligament to communicate with those in the bone ence of molecules typical of hyaline cartilage (aggrecan, marrow (fig 5F). link protein, and type II collagen—see the review by The tips of the bony spurs seen at the lateral epicondyle in Benjamin and McGonagle14), and the local absence of two of the six specimens, were covered with fibrocartilage those typical of fibrous tissue (type I collagen and versi- (fig 5G) and in one of these, islands of fibrocartilage were can23 31). The normal presence of fibrocartilage in the present within the bone itself, between adjacent bone epicondylar entheses is in line with the report of Putz et al,31 spicules (fig 5H). In the same cadaver, there was a small who commented on it at the collateral ligament entheses in bone cyst (fig 5I). Although evidence of inflammation was their general account of the functional anatomy of the elbow rare, inflammatory cells were occasionally present around joint. small venules in the bone marrow (fig 5J). This was Histopathological changes similar to those described in accompanied by some evidence of bone marrow fibrosis reports on epicondylitis—notably, fibrovascular prolifera- (fig 5K), possibly indicating previous inflammation at those tion,10 32 33 focal calcifications,934and ‘‘mucoid degeneration’’ sites. or fibrocartilage proliferation,4 were seen in both the ligamentous and tendinous parts of the medial and lateral DISCUSSION epicondylar entheses. As in epicondylitis, the majority of The purpose of this study was to describe the normal changes seen in elderly cadavers were degenerative rather structure and molecular composition of entheses implicated than inflammatory. The widespread nature of such changes in epicondylitis, and to highlight the presence of degenerative suggests that degeneration is normal in elderly people. This is changes in elderly subjects that are similar to those described in line with the earlier findings of Kumagai et al on the 35 by others in patients with tennis or golfer’s elbow. As in all rotator cuff entheses of older subjects. Our findings also studies of this type, there might have been undocumented suggest that there are no histopathological changes that can episodes of epicondylitis earlier in the subjects’ lives, despite be regarded as specific to epicondylitis. All the major changes our efforts to select ‘‘normal’’ elbows’. However, this is described by other authors in patients with epicondylitis (see unlikely to be a significant issue, as the general incidence of above) have also been seen by us in the entheses of elderly epicondylitis is less than 1%.18 subjects. We suggest that fibrocartilage proliferation in We showed that (a) tendon entheses on both the medial epicondylitis reflects the importance of mechanical forces in 236 and lateral sides of the elbow formed complex structures that understanding the causative factors of these conditions. were totally integrated with the attachments of the respective Mechanical overload may also induce bony spur formation in collateral ligaments. Thus, abnormality in the tendon or lateral epicondylar enthesis fibrocartilage—as in the dorsal 24 ligament is likely to affect the other, and both may be capsule of the lumbar facet joints. However, it must be involved in epicondylitis. This may be why some cases of accepted that some epidemiological data on epicondylitis are epicondylitis are refractory to tenodesis19–22;(b) fibrocartilage conflicting and do not always suggest a close link with 18 is a constant feature of all entheses from subjects of a wide strenuous manual work. http://ard.bmj.com/ age range and its mere presence cannot be considered as We have shown that aggrecan and link protein are present ‘‘pathological’’ itself; (c) entheses from elderly people can in all enthesis fibrocartilages examined, as in several other show extensive microscopic evidence of degeneration, regions of the body (see the review by Benjamin and hitherto equated specifically with epicondylitis. McGonagle14). As cleavage of aggrecan by matrix metallo- From a clinical perspective, epicondylitis is sometimes proteinases is a feature of cartilage degeneration,37 this associated with pain and tenderness adjacent to the tendon probably contributes to ‘‘mucoid (mucinoid) degeneration’’ 5 at epicondylar entheses.2 Because link protein is known to be attachments, and degenerative changes have been reported on September 28, 2021 by guest. Protected copyright. in the collateral ligament by magnetic resonance imaging and an antigenic target for autoimmune responses in rheumatoid sonography.46We think the involvement of structures other arthritis,38–40 it is possible that some cases of epicondylitis than the tendon enthesis, partly reflects the complex nature may also be related to this condition. It is pertinent to of the attachment sites that we have described. On both note that Lehtinen et al have shown that the lateral epicondyles the tendon and ligament attachments merged epicondyle is affected by erosion in 78% of patients with a imperceptibly with each other and had a similar labelling 15 year history of seropositive and erosive rheumatoid profile for molecules found in numerous other fibrocartila- arthritis.41 Finally, although lateral epicondylitis is usually ginous entheses.14 16 23–27 This is the first demonstration of regarded as idiopathic, it is worth noting that the lateral fusion between the tendons and the collateral ligaments at epicondylar enthesis has been listed among the most their entheses, but a close association has been noted commonly affected in patients with spondyloarthropathy.42 previously by surgical anatomists and radiologists.4 Many of This may also have a bearing on autoimmune responses to the older gross anatomy texts, in particular, comment on fibrocartilage antigens.43 such matters. Thus, both Strasser28 and Robinson29 pointed In summary, we conclude that fibrocartilage is a normal out that the collateral ligaments are intimately associated feature of epicondylar entheses that should not merely be with the muscles which originate from the medial and lateral equated with pathological change. Furthermore, none of the epicondyles, and Ru¨dinger30 noted that the extensor carpi degenerative changes previously associated with epicondylitis radialis brevis is attached to the joint capsule and can put are specific to those diseases, but can also be a sign of aging. tension upon it. We contend that on both sides of the elbow, Finally, clinical observations of diffuse pain and tenderness the conjoined tendon-ligament enthesis created a wide in epicondylitis (that is, that which extends locally beyond insertional area that can be viewed as part of an ‘‘enthesis the actual tendon enthesis to bone) may relate to the organ’’ that dissipates stress concentration away from a small complex nature of the attachment site and the presence of an focal point.14 enthesis organ.

www.annrheumdis.com Molecular composition and pathology of entheses of the humerus 1021 Ann Rheum Dis: first published as 10.1136/ard.2003.016378 on 12 August 2004. Downloaded from ACKNOWLEDGEMENTS 17 Rufai A, Ralphs JR, Benjamin M. Structure and histopathology of the This work was supported by Action Medical Research and Search. insertional region of the human Achilles tendon. J Orthop Res 1995;13:585–93. Professor McGonagle is an MRC clinical scientist and Professor 18 Viikari-Juntura E. The role of physical stresses in the development of hand/ Emery is an ARC professor of rheumatology. wrist and elbow disorders. In: Gordon SL, Blair SJ, Fine LJ, eds. Repetitive motion disorders of the upper extremity. Illinois: Amer Acad Orthop Surg, ...... 1995:7–30. 19 Grundberg AB, Dobson JF. Percutaneous release of the common extensor Authors’ affiliations origin for tennis elbow. Clin Orthop 2000;376:137–40. 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